A major challenge in vaccinology is that the efficacy of a vaccine can only be ascertained retrospectively, upon infection. The identification of molecular signatures induced rapidly after vaccination, which correlate with and predict, the later development of protective immune responses, would represent a strategy to prospectively determine vaccine efficacy. Such a strategy would be particularly useful when evaluating the efficacy or immunogenicity of untested vaccines, or in identifying individuals with sub-optimal responses amongst high risk populations such as infants or the elderly. We and others have recently used a systems biology approach to identify early gene signatures that correlate with, and predict the later immune responses in humans vaccinated with the live attenuated yellow fever vaccine YFV-17D. Despite this promising advance, the extent to which such approaches can reveal the immunological mechanisms of action of vaccines, and help discover new correlates of protective immunity, remains untested. Furthermore, the potential public health impact of these strategies in predicting the immunogenicity, or even efficacy, of vaccines that induce sub-optimal responses in immunocompromised populations such as the elderly, needs to be rigorously evaluated. Within this context, the aims of the present grant are: Aim 1: Systems biological approaches to identify molecular signatures that predict the sub-optimal immunogenicity of the herpes zoster vaccine, a pneumococcal polysaccharide vaccine (PPV23), and the trivalent inactivated influenza vaccine (TIV) Aim 2: Systems biological analysis of transcriptional and micro RNA networks in dendritic cells from young versus elderly, stimulated in vitro with the herpes zoster vaccine, PPV23 and TIV. Aim 3: Systems biological analysis of innate responses during herpes zoster re-activation, and during acute infections caused by Streptococcus pneumoniae The successful completion of these aims will: (i) address important public health concerns regarding impaired immunogenicity of these vaccines in the elderly (ii) provide biological insight into novel innate correlates of immunity, and (iii) represent the first comprehensive evaluation of immune responses to any vaccine in the elderly versus young.